ABSTRACT
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzazepines/chemical synthesis , Cell Cycle Proteins/antagonists & inhibitors , Lactams/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Thiones/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Lactams/pharmacokinetics , Lactams/pharmacology , Mice , Mice, Nude , Mitosis , Models, Molecular , Neoplasm Transplantation , Protein Conformation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiones/pharmacokinetics , Thiones/pharmacology , Transplantation, Heterologous , Polo-Like Kinase 1ABSTRACT
4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
